Pharmaceutical composition comprising (1r,4r)-6&#39;-fluoro-n,n-dimethyl-4-phenyl-4&#39;,9&#39;-dihydro-3&#39;h-spiro [cyclohexane-1,1&#39;-pyrano-[3,4,b]indol]-4-amine and paracetamol or propacetamol

ABSTRACT

The invention relates to a pharmaceutical composition comprising a first pharmacologically active ingredient selected from (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and the physiologically acceptable salts thereof, and a second pharmacologically active ingredient selected from paracetamol and propacetamol.

This application is a continuation of U.S. patent application Ser. No.15/726,761, filed Oct. 6, 2017, which is a continuation of U.S. patentapplication Ser. No. 13/892,969, filed May 13, 2013, now abandoned,which: (i) claims the benefit of U.S. Provisional Patent Application No.61/648,732, filed May 18, 2012; and (ii) claims foreign priority benefitunder 35 U.S.C. § 119 of European Patent Application No. 12 003 897.1,filed May 18, 2012, the entire contents of each of which areincorporated herein by reference.

The invention relates to a pharmaceutical composition comprising a firstpharmacologically active ingredient selected from(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand the physiologically acceptable salts thereof, and a secondpharmacologically active ingredient selected from paracetamol andpropacetamol.

(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]-indol]-4-amineand its corresponding physiologically acceptable salts as well asmethods for their preparation are well known, for example, fromWO2004/043967 and WO2008/040481. The compounds exhibit analgesicproperties and are particularly suitable for the treatment of acute,visceral, neuropathic or chronic (nociceptive) pain.

Paracetamol (acetaminophen) and its prodrug, propacetamol, are widelyused for the treatment of various pain conditions.

Though both of the aforementioned substance classes can be used in theprevention and treatment of pain and are as such therapeuticallyeffective, side effects may occur, especially upon prolonged use or whenadministered at high dosages.

It is further known that specific combinations of pharmacologicallyactive compounds exert supra-additive (synergistic) therapeutic effectsupon administration. An advantage of these special cases is that theoverall dose and accordingly the risk of undesired side effects may bereduced.

In a further aspect, two pharmacologically active compounds exerting asynergistic effect may be combined in one single pharmaceutical dosageform, e.g. a tablet, thus enhancing patient compliance.

It is an object of the invention to provide pharmaceutical compositionswhich have advantages compared to pharmaceutical compositions of theprior art. In particular, the pharmaceutical compositions should providerapid therapeutic effects, but also should have a high tolerability,good compliance and safety.

This object has been achieved by the subject-matter of the patentclaims.

It has been surprisingly found that a pharmaceutical compositioncomprising(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand paracetamol or its prodrug propacetamol is useful for the treatmentof acute and chronic pain.

Further it has been surprisingly found that said composition exhibits asynergistic therapeutic effect upon administration. Therefore, theoverall administered dose may be lowered, so that fewer undesiredside-effects will occur.

A first aspect of the invention relates to a pharmaceutical compositioncomprising:

-   -   (a) a first pharmacologically active ingredient selected from        (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine        and the physiologically acceptable salts thereof, and    -   (b) a second pharmacologically active ingredient selected from        paracetamol and propacetamol.

The pharmaceutical composition according to the invention comprises afirst pharmacologically active ingredient selected from(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand the physiologically acceptable salts thereof.

For the purpose of specification,(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine is the compound according to formula (I) which canalso be referred to as1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole(trans)

The definition of the first pharmacologically active ingredient includes(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I), inany possible form including solvates, cocrystals and polymorphs, and itsphysiologically acceptable salts, in particular acid addition salts andcorresponding solvates, cocrystals and polymorphs.

The pharmacologically active ingredient(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminemay be present in the pharmaceutical composition according to theinvention in form of a physiologically acceptable salt, preferably anacid addition salt, whereby any suitable acid capable of forming such anaddition salt may be used.

The conversion of(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclo-hexane-1,1′-pyrano[3,4,b]indol]-4-amineinto a corresponding addition salt, for example, via reaction with asuitable acid may be effected in a manner well known to those skilled inthe art. Suitable acids include but are not limited to hydrochloricacid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formicacid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelicacid, fumaric acid, lactic acid, citric acid, glutamic acid and/oraspartic acid. Salt formation is preferably effected in a solvent, forexample, diethyl ether, diisopropyl ether, alkyl acetates, acetoneand/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solutionis also suitable for the preparation of hydrochlorides.

In a preferred embodiment, the first pharmacologically active ingredientis(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3+H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I).

In another preferred embodiment, the first pharmacologically activeingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3+H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineamine in form of a physiologically acceptable acid addition salt, inparticular the hydrochloride, hemicitrate or maleate salt.

Unless explicitly stated otherwise, all amounts of the firstpharmacologically active ingredient specified in the following are givenaccording to the corresponding amount of(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I).

The pharmaceutical composition according to the invention comprises asecond pharmacologically active ingredient selected from paracetamol andpropacetamol.

Paracetamol and propacetamol have the structures according to formulas(II) and (III), respectively:

The definition of the second pharmacologically active ingredientincludes the compounds paracetamol and propacetamol in any possible formincluding solvates, cocrystals and polymorphs.

In a preferred embodiment, the second pharmacologically activeingredient is paracetamol.

In another preferred embodiment, the second pharmacologically activeingredient is propacetamol.

In a preferred embodiment, the first pharmacologically active ingredientis(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine in form of the free base, i.e. the compound according toformula (I), and the second pharmacologically active ingredient isselected from paracetamol and propacetamol.

In another preferred embodiment, the first pharmacologically activeingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of a physiologically acceptable acid addition salt, inparticular the hydrochloride, hemicitrate or maleate salt, and thesecond pharmacologically active ingredient is selected from paracetamoland propacetamol.

In a preferred embodiment, the first pharmacologically active ingredientis(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of a physiologically acceptable acid addition salt, inparticular the hydrochloride, hemicitrate or maleate salt, and thesecond pharmacologically active ingredient is paracetamol.

In another preferred embodiment, the first pharmacologically activeingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the free base, i.e. the compound according to formula (I),and the second pharmacologically active ingredient is paracetamol.

Another aspect of the invention relates to a pharmaceutical dosage formcomprising the pharmaceutical composition according to the invention.

The first and the second pharmacologically active ingredient aretypically contained in the pharmaceutical dosage form according to theinvention in a therapeutically effective amount. The amount thatconstitutes a therapeutically effective amount varies according to thepharmacologically active ingredients, the condition being treated, theseverity of said condition, the patient being treated, and whether thepharmaceutical dosage form is designed for an immediate or controlledrelease.

In a preferred embodiment, the content of the first pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at most 10 wt.-% or at most 5 wt.-% or at most 3 wt.-%or at most 1.0 wt.-%, more preferably at most 0.8 wt.-%, yet morepreferably at most 0.5 wt.-%, still more preferably at most 0.2 wt.-%,even more preferably at most 0.1 wt.-%, most preferably at most 0.05wt.-%, and in particular at most 0.01 wt.-% or at most 0.005 wt.-% or atmost 0.001 wt.-%.

In a preferred embodiment, the content of the second pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at most 95 wt.-%, more preferably at most 80 wt.-%, yetmore preferably at most 70 wt.-%, still more preferably at most 60wt.-%, even more preferably at most 55 wt.-%, most preferably at most 50wt.-%, and in particular at most 45 wt.-%.

In a preferred embodiment, the content of the first pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at least 0.0001 wt.-%, more preferably at least 0.0003wt.-%, yet more preferably at least 0.0005 wt.-%, still more preferablyat least 0.0008 wt.-%, even more preferably at least 0.001 wt.-%, mostpreferably at least 0.003 wt.-%, and in particular at least 0.005 wt.-%.

In a preferred embodiment, the content of the second pharmacologicallyactive ingredient in the pharmaceutical dosage form according to theinvention and the pharmaceutical composition according to the invention,respectively, is at least 0.1 wt.-%, more preferably at least 0.5 wt.-%,yet more preferably at least 1 wt.-%, still more preferably at least 3wt.-%, even more preferably at least 5 wt.-%, most preferably at least7.5 wt.-%, and in particular at least 10 wt.-%.

Unless explicitly stated otherwise, in the meaning of the invention theindication “wt.-%” shall mean weight of the respective ingredient pertotal weight of the pharmaceutical dosage form or per total weight ofthe pharmaceutical composition, respectively.

Preferably, in the pharmaceutical dosage form according to the inventionand the pharmaceutical composition according to the invention,respectively, the relative weight ratio of the first pharmacologicallyactive ingredient to the second pharmacologically active ingredient iswithin the range of from 1:2 to 1:1,000,000, more preferably 1:30 to1:1,000,000, still more preferably 1:100 to 1:1,000,000, most preferably1:1,000 to 1:500,000, and in particular 1:2,000 to 1:300,000.

In a preferred embodiment, in the pharmaceutical dosage form accordingto the invention and the pharmaceutical composition according to theinvention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100 to 1:10,000, morepreferably 1:200 to 1:7,500, still more preferably 1:500 to 1:5,000,most preferably 1:750 to 1:2,500, and in particular 1:900 to 1:2,000.

In another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:1,000 to 1:20,000, morepreferably 1:2,000 to 1:15,000, still more preferably 1:3,000 to1:12,500, yet more preferably 1:4,000 to 1:12,000, most preferably1:5,000 to 1:10,000, and in particular 1:6,000 to 1:9,000.

In still another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:1,000 to 1:100,000, morepreferably 1:2,000 to 1:80,000, still more preferably 1:4,000 to1:50,000, yet more preferably 1:6,000 to 1:20,000, most preferably1:8,000 to 1:15,000, and in particular 1:9,000 to 1:12,500.

In yet another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:5,000 to 1:500,000, morepreferably 1:10,000 to 1:400,000, still more preferably 1:20,000 to1:300,000, most preferably 1:40,000 to 1:200,000, and in particular1:50,000 to 1:100,000.

In a further preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative weight ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100,000 to 1:1,900,000,more preferably 1:250,000 to 1:1,800,000, still more preferably1:300,000 to 1:700,000, most preferably 1:350,000 to 1:650,000, and inparticular 1:400,000 to 1:600,000.

Preferably, in the pharmaceutical dosage form according to the inventionand the pharmaceutical composition according to the invention,respectively, the relative molar ratio of the first pharmacologicallyactive ingredient to the second pharmacologically active ingredient iswithin the range of from 1:2 to 1:1,000,000, more preferably 1:30 to1:1,000,000, still more preferably 1:100 to 1:1,000,000, most preferably1:1,000 to 1:500,000, and in particular 1:2,000 to 1:300,000.

In a preferred embodiment, in the pharmaceutical dosage form accordingto the invention and the pharmaceutical composition according to theinvention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100 to 1:10,000, morepreferably 1:200 to 1:7,500, still more preferably 1:500 to 1:5,000,most preferably 1:750 to 1:2,500, and in particular 1:900 to 1:2,000.

In another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:1,000 to 1:20,000, morepreferably 1:2,000 to 1:15,000, still more preferably 1:3,000 to1:12,500, yet more preferably 1:4,000 to 1:12,000, most preferably1:5,000 to 1:10,000, and in particular 1:6,000 to 1:9,000.

In still another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:1,000 to 1:100,000, morepreferably 1:2,000 to 1:80,000, still more preferably 1:4,000 to1:50,000, yet more preferably 1:6,000 to 1:20,000, most preferably1:8,000 to 1:15,000, and in particular 1:9,000 to 1:12,500.

In yet another preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:5,000 to 1:500,000, morepreferably 1:10,000 to 1:400,000, still more preferably 1:20,000 to1:300,000, most preferably 1:40,000 to 1:200,000, and in particular1:50,000 to 1:100,000.

In a further preferred embodiment, in the pharmaceutical dosage formaccording to the invention and the pharmaceutical composition accordingto the invention, respectively, the relative molar ratio of the firstpharmacologically active ingredient to the second pharmacologicallyactive ingredient is within the range of from 1:100,000 to 1:1,900,000,more preferably 1:250,000 to 1:1,800,000, still more preferably1:300,000 to 1:700,000, most preferably 1:350,000 to 1:650,000, and inparticular 1:400,000 to 1:600,000.

The amounts of the first and the second pharmacologically activeingredient contained in the pharmaceutical dosage form according to theinvention may vary depending on different factors well known to thoseskilled in the art, for example, the weight of the patient, the route ofadministration, the severity of the illness and the like.

In general, both pharmacologically active ingredients contained in thepharmaceutical dosage form according to the invention may beadministered in amounts up to their maximum daily dose, which is knownto those skilled in the art. As the second pharmacologically activeingredient, paracetamol may preferably be administered to a patient in amaximum daily dose of up to 4,000 mg, and propacetamol may preferably beadministered to a patient in a maximum daily dose of up to 8,000 mg.

When administered in the prescribed manner, e.g. once daily or twicedaily, the pharmaceutical dosage form according to the invention and thepharmaceutical composition according to the invention, respectively,preferably contain the first and the second pharmacologically activeingredient, independently of one another, in an amount corresponding to75±15 wt.-%, 75±10 wt.-%, 75±5 wt.-%, 50±15 wt.-%, 50±10 wt.-%, 50±5wt.-%, 25±15 wt.-%, 25±10 wt.-% or 25±5 wt.-% of the respective maximumdaily dose of the first and the second pharmacologically activeingredient, respectively.

Preferably, the pharmaceutical dosage form according to the inventioncontains the first pharmacologically active ingredient in a dose of from0.1 μg to 5,000 μg, more preferably, 0.1 μg to 2,500 μg, still morepreferably 1.0 μg to 1,000 μg, yet more preferably 10 to 800 μg, mostpreferably 15 μg to 600 μg, and in particular 20 μg to 440 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains the first pharmacologically active ingredient ina dose within the range of 13±12 μg, more preferably 13±10 μg, stillmore preferably 13±8 μg, yet more preferably 13±6 μg, even morepreferably 13±5 μg, most preferably 13±4 μg, and in particular 13±3 μg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 20±15 μg, more preferably 20±13μg, still more preferably 20±12 μg, yet more preferably 20±10 μg, evenmore preferably 20±8 μg, most preferably 20±6 μg, and in particular 20±5μg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 40±35 μg, more preferably 40±30μg, still more preferably 40±25 μg, yet more preferably 40±20 μg, evenmore preferably 40±15 μg, most preferably 40±10 μg, and in particular40±5 μg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 60±50 μg, more preferably 60±40μg, still more preferably 60±30 μg, yet more preferably 60±20 μg, mostpreferably 60±10 μg, and in particular 60±5 μg.

In a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 80±70 μg, more preferably 80±60μg, still more preferably 80±50 μg, yet more preferably 80±40 μg, evenmore preferably 80±20 μg, most preferably 80±10 μg, and in particular80±5 μg.

In still a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 100±90 μg, more preferably100±80 μg, still more preferably 100±60 μg, yet more preferably 100±40μg, even more preferably 100±20 μg, most preferably 100±10 μg, and inparticular 100±5 μg.

In yet a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 120±100 μg, more preferably120±80 μg, still more preferably 120±60 μg, yet more preferably 120±40μg, even more preferably 120±20 μg, most preferably 120±10 μg, and inparticular 120±5 μg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 150±90 μg, more preferably150±80 μg, still more preferably 150±60 μg, yet more preferably 150±40μg, even more preferably 150±20 μg, most preferably 150±10 μg, and inparticular 150±5 μg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 170±130 μg, more preferably170±100 μg, still more preferably 170±80 μg, yet more preferably 170±60μg, even more preferably 170±40 μg, most preferably 170±20 μg, and inparticular 170±10 μg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 200±175 μg, more preferably200±150 μg, still more preferably 200±125 μg, yet more preferably200±100 μg, even more preferably 200±75 μg, most preferably 200±50 μg,and in particular 200±25 μg.

In a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 400±350 μg, more preferably400±300 μg, still more preferably 400±250 μg, yet more preferably400±200 μg, even more preferably 400±150 μg, most preferably 400±100 μg,and in particular 400±50 μg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 600±400 μg, more preferably600±300 μg, still more preferably 600±250 μg, yet more preferably600±200 μg, even more preferably 600±150 μg, most preferably 600±100μpg, and in particular 600±50 μg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 800±550 μg, more preferably800±400 μg, still more preferably 800±350 μg, yet more preferably800±250 μg, even more preferably 800±150 μg, most preferably 800±100 μg,and in particular 800±50 μg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 1,000±800 μg, more preferably1,000±600 μg, still more preferably 1,000±500 μg, yet more preferably1,000±300 μg, even more preferably 1,000±200 μg, most preferably1,000±100 μg, and in particular 1,000±50 μg.

In a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the first pharmacologically activeingredient in a dose within the range of 1,200±1,000 μg, more preferably1,200±800 μg, still more preferably 1,200±600 μg, yet more preferably1,200±400 μg, even more preferably 1,200±200 μg, most preferably1,200±100 μg, and in particular 1,200±50 μg.

Preferably, the pharmaceutical dosage form according to the inventioncontains the second pharmacologically active ingredient in a dose offrom 1.0 mg to 12,500 mg, more preferably, 10 mg to 10,000 mg, and mostpreferably 100 mg to 8,000 mg, and in particular 200 mg to 7,000 mg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains the second pharmacologically active ingredient ina dose within the range of 150±120 mg, more preferably 150±100 mg, stillmore preferably 150±90 mg, yet more preferably 150±75 mg, even morepreferably 150±60 mg, most preferably 150±50 mg, and in particular150±25 mg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 300±250 mg, more preferably300±200 mg, still more preferably 300±150 mg, yet more preferably300±125 mg, even more preferably 300±100 mg, most preferably 300±75 mg,and in particular 300±50 mg.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 500±400 mg, more preferably500±300 mg, still more preferably 500±200 mg, yet more preferably500±150 mg, even more preferably 500±100 mg, most preferably 500±75 mg,and in particular 500±50 mg.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 750±500 mg, more preferably750±400 mg, still more preferably 750±250 mg, yet more preferably750±100 mg, even more preferably 750±75 mg, most preferably 750±50 mg,and in particular 750±25 mg.

In a further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 1,000±500 mg, more preferably1,000±400 mg, still more preferably 1,000±250 mg, yet more preferably1,000±100 mg, even more preferably 1,000±75 mg, most preferably 1,000±50mg, and in particular 1,000±25 mg.

In a still further preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 1,500±500 mg, more preferably1,500±400 mg, still more preferably 1,500±250 mg, yet more preferably1,500±100 mg, even more preferably 1,500±75 mg, most preferably 1,500±50mg, and in particular 1,500±25 mg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains the second pharmacologically active ingredient ina dose within the range of 1,800±1,000 mg, more preferably 1,800±750 mg,still more preferably 1,800±500 mg, yet more preferably 1,800±300 mg,even more preferably 1,800±200 mg, most preferably 1,800±100 mg, and inparticular 1,800±50 mg.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the second pharmacologically activeingredient in a dose within the range of 2,000±1,000 mg, more preferably2,000±750 mg, still more preferably 2,000±500 mg, yet more preferably2,000±300 mg, even more preferably 2,000±200 mg, most preferably2,000±100 mg, and in particular 2,000±50 mg.

In a preferred embodiment, the pharmaceutical dosage form containsparacetamol as the second pharmacologically active ingredient in a dosewithin the range of 100 mg to 1,500 mg, more preferably in the range of200 mg to 1,200 mg, even more preferably in the range of 250 mg to 900mg, most preferably in the range of 300 mg to 750 mg and in particularin the range of 400 mg to 600 mg.

In another preferred embodiment, the pharmaceutical dosage form containsparacetamol as the second pharmacologically active ingredient in a dosewithin the range of 200 mg to 2,000 mg, more preferably in the range of400 mg to 1,800 mg, even more preferably in the range of 600 mg to 1,500mg, most preferably in the range of 750 mg to 1,300 mg, and inparticular in the range of 800 mg to 1,200 mg.

In a further preferred embodiment, the pharmaceutical dosage formcontains paracetamol as the second pharmacologically active ingredientin a dose within the range of 500 mg to 4,000 mg, more preferably in therange of 1,000 mg to 3,000 mg, even more preferably in the range of1,400 mg to 2,600 mg, most preferably in the range of 1,600 mg to 2,400mg, and in particular in the range of 1,800 mg to 2,200 mg.

In a preferred embodiment, the pharmaceutical dosage form containspropacetamol as the second pharmacologically active ingredient in a dosewithin the range of 200 mg to 2,000 mg, more preferably in the range of400 mg to 1,800 mg, even more preferably in the range of 600 mg to 1,500mg, most preferably in the range of 750 mg to 1,300 mg, and inparticular in the range of 800 mg to 1,200 mg.

In another preferred embodiment, the pharmaceutical dosage form containspropacetamol as the second pharmacologically active ingredient in a dosewithin the range of 500 mg to 3,000 mg, more preferably in the range of800 mg to 2,400 mg, even more preferably in the range of 1,000 mg to2,000 mg, most preferably in the range of 1,200 mg to 1,750 mg, and inparticular in the range of 1,400 mg to 1,600 mg.

In still another preferred embodiment, the pharmaceutical dosage formcontains propacetamol as the second pharmacologically active ingredientin a dose within the range of 500 mg to 4,000 mg, more preferably in therange of 750 mg to 3,500 mg, even more preferably in the range of 1,000mg to 3,000 mg, most preferably in the range of 1,500 mg to 2,500 mg,and in particular in the range of 1,800 mg to 2,200 mg.

In the pharmaceutical dosage form according to the invention, the doseof the first pharmacologically active ingredient is preferably withinthe range of from 1:20 to 20:1 of the amount which is equieffective tothe dosage of the second pharmacologically active ingredient. In thisregard, “equieffective” preferably means the dosage that would berequired in order to achieve the equivalent desired therapeutic effectwhen being administered alone. A skilled person recognizes that when thedesired therapeutic effect is an analgesic effect, the equieffectivedosage is determined with respect to the analgesic properties of thefirst pharmacologically active ingredient and the second pharmacologicalingredient.

For example, when the dose of the second pharmacologically activeingredient, which is contained in the pharmaceutical dosage formaccording to the invention, amounts to e.g. 30 mg and provides ananalgesic effect E when being administered alone at this dose, and whenthe equieffective amount of the first pharmacologically activeingredient, i.e. the amount needed in order to provide the sameanalgesic effect E when being administered alone, would be e.g. 4 μg,the dosage of the first pharmacologically active ingredient, which iscontained in the pharmaceutical dosage form according to the invention,may vary from 0.2 μg (4 μg/20) to 80 μg (20.4 μg).

In a preferred embodiment, the dose of the first pharmacologicallyactive ingredient is within the range of from 1:15 to 15:1, preferablywithin the range of from 1:10 to 10:1, more preferably within the rangeof from 1:8 to 8:1, still more preferably within the range of from 1:6to 6:1, yet more preferably within the range of from 1:4 to 4:1, mostpreferably within the range of from 1:3 to 3:1, and in particularpreferably within the range of from 1:2 to 2:1, of the amount which isequieffective to the dose of the second pharmacologically activeingredient.

Suitable pathways of administration of the pharmaceutical dosage formaccording to the invention include but are not limited to oral,intravenous, intraperitoneal, intradermal, transdermal, intrathecal,intramuscular, intranasal, transmucosal, subcutaneous, local and/orrectal administration.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for oral administration.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for parenteral administration, inparticular intravenous, intraperitoneal, intrathecal, intramuscular, orsubcutaneous administration.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for rectal administration.

The pharmaceutical dosage form according to the invention and thepharmaceutical composition according to the invention, respectively, canbe solid, semi-solid or liquid.

The pharmaceutical dosage form according to the invention and thepharmaceutical composition according to the invention, respectively, maycontain auxiliary agents, for example, carriers, fillers, solvents,diluents, colorants and/or binders. The selection of auxiliary agentsand of the amounts of the same to be used depends, for example, on howthe first and the second pharmacologically active ingredient are to beadministered, e.g. orally, intravenously, intraperitoneally,intradermally, transdermally, intrathecally, intramuscularly,intranasally, transmucosally, subcutaneously, rectally or locally.

Suitable auxiliary agents are in particular any substances known to aperson skilled in the art useful for the preparation of galenical dosageforms. Examples of suitable auxiliary agents include but are not limitedto: water, ethanol, 2-propanol, glycerol, ethylene glycol, propyleneglycol, polyethylene glycol, polypropylene glycol, glucose, fructose,lactose, saccharose, dextrose, molasses, starch, modified starch,gelatine, sorbitol, inositol, mannitol, microcrystalline cellulose,methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac,cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes, natural andsynthetic gums, acacia gum, alginates, dextran, saturated andunsaturated fatty acids, stearic acid, magnesium stearate, zincstearate, glycerol stearate, sodium lauryl sulphate, edible oils, sesameoil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate,polyoxyethylene and polypropylene fatty acid ester, sorbitan fatty acidester, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannicacid, sodium chloride, potassium chloride, magnesium chloride, calciumchloride, magnesium oxide, zinc oxide, silicon dioxide, titanium oxide,titanium dioxide, magnesium sulphate, zinc sulphate, calcium sulphate,potash, calcium phosphate, dicalcium phosphate, potassium bromide,potassium iodide, talcum, kaolin, pectin, crosspovidone, agar andbentonite.

Pharmaceutical dosage forms which are suitable for oral administrationinclude but are not limited to tablets, effervescent tablets, chewingtablets, dragees, capsules, drops, juices and syrups. Oralpharmaceutical dosage forms may also be in the form of multiparticulatessuch as granules, pellets, spheres, crystals and the like, optionallycompressed into a tablet, filled into a capsule, filled into a sachet orsuspended in a suitable liquid medium. Oral pharmaceutical dosage formsmay also be equipped with an enteric coating.

Pharmaceutical dosage forms that are suitable for parenteral, topicaland inhalative administration include but are not limited to solutions,suspensions, easily reconstitutable dry preparations and sprays.

Suppositories are a suitable pharmaceutical dosage form for rectaladministration. Dosage forms in a deposit, in dissolved form, forexample, in a patch optionally with the addition of agents to promoteskin penetration, are examples of suitable dosage forms for percutaneousadministration.

In an especially preferred embodiment, the pharmaceutical dosage formaccording to the invention is a tablet.

Preferably, the pharmaceutical dosage form according to the invention isfor administration six times daily, five times daily, four times daily,thrice daily, twice daily, once daily, or less frequently.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for administration once daily.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration multiple daily, inparticular twice daily, thrice daily, or up to six times a day.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for administration twice daily.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration thrice daily.

For the purpose of specification, “administration thrice daily” (tid)preferably means that the pharmaceutical dosage form according to theinvention is adapted for being consecutively administered according to aregimen comprising the administration of three pharmaceutical dosageforms per day, wherein the time interval between the consecutiveadministration of two pharmaceutical dosage forms is at least 3 hours,preferably at least 4 hours, more preferably not least 6 hours and inparticular, about 8 hours.

For the purpose of specification, “administration twice daily” (bid)preferably means that the pharmaceutical dosage form according to theinvention is adapted for being consecutively administered according to aregimen comprising the administration of two pharmaceutical dosage formsper day, wherein the time interval between the consecutiveadministration of two pharmaceutical dosage forms is at least 6 hours,preferably at least 8 hours, more preferably at least 10 hours and inparticular, about 12 hours.

For the purpose of specification, “administration once daily” (sid)preferably means that the pharmaceutical dosage form according to theinvention is adapted for being consecutively administered according to aregimen comprising the administration of one pharmaceutical dosage formper day, wherein the time interval between the consecutiveadministration of two pharmaceutical dosage forms is at least 18 hours,preferably at least 20 hours, more preferably at least 22 hours and inparticular, about 24 hours.

A skilled person is fully aware that the above administration regimensmay be realized by administering a single pharmaceutical dosage formcontaining the full amount of the first pharmacologically activeingredient and the full amount of the second pharmacologically activeingredient to be administered at a particular point in time or,alternatively, administering a multitude of dose units, i.e. two, threeor more dose units, the sum of which multitude of dose units containingthe full amount of the first pharmacologically active ingredient and thesecond pharmacologically active ingredient to be administered at saidparticular point in time, where the individual dose units are adaptedfor simultaneous administration or administration within a short periodof time, e.g. within 5, 10 or 15 minutes.

In the following, the doses of the first and the secondpharmacologically active ingredient are expressed according to thenumber of prescribed administrations “n” per day, i.e. the number ofadministrations of the pharmaceutical dosage form according to theinvention in the course of 24 hours. As an example, 100/n μg in case ofan administration once daily (n=1) corresponds to a dose of 100 μg, and100/n μg in case of an administration twice daily (n=2) corresponds to adose of 50 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for administration once daily (n=1), wherein thepharmaceutical dosage form contains the first pharmacologically activeingredient in a dose of from 15/n to 100/n μg, preferably 20/n to 80/nμg, and the second pharmacologically active ingredient in a dose of from1,000/n to 8,000/n mg. According to this embodiment, the pharmaceuticaldosage form according to the invention is preferably for oraladministration, preferably in form of a tablet.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration multiple daily (n=2, 3,4, 5 or 6), wherein the pharmaceutical dosage form contains the firstpharmacologically active ingredient in a dose of from 15/n to 100/n μg,preferably 20/n to 80/n μg, and the second pharmacologically activeingredient in a dose of from 1,000/n to 8,000/n mg. According to thisembodiment, the pharmaceutical dosage form according to the invention ispreferably for oral administration, preferably in form of a tablet.Further, according to this embodiment, an administration thrice daily(n=3) or four times daily (n=4), in particular of paracetamol, can beespecially preferred since the preferred dose of paracetamol may be ashigh as 4,000/n mg, thus rendering a tablet containing e.g. a maximum of4,000/3 mg or 4,000/4 mg of paracetamol much more patient compliant.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration once daily (n=1),wherein the pharmaceutical dosage form contains the firstpharmacologically active ingredient in a dose of from 150/n to 1,200/nμg, preferably 200/n to 800/n μg, and the second pharmacologicallyactive ingredient in a dose of from 1,000/n to 8,000/n mg. According tothis embodiment, the pharmaceutical dosage form according to theinvention is preferably for oral administration, preferably in form of atablet.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration multiple daily (n=2, 3,4, 5 or 6), wherein the pharmaceutical dosage form contains the firstpharmacologically active ingredient in a dose of from 150/n to 1,200/nμg, preferably 200/n to 800/n μg, and the second pharmacologicallyactive ingredient in a dose of from 1,000/n to 8,000/n mg. According tothis embodiment, the pharmaceutical dosage form according to theinvention is preferably for oral administration, preferably in form of atablet. Further, according to this embodiment, an administration thricedaily (n=3) or four times daily (n=4), in particular of paracetamol, canbe especially preferred since the preferred dose of paracetamol may beas high as 4,000/n mg, thus rendering a tablet containing e.g. a maximumof 4,000/3 mg or 4,000/4 mg of paracetamol much more patient compliant.

The pharmaceutical dosage form according to the invention may provideunder in vitro conditions immediate release or controlled release of thefirst pharmacologically active ingredient and/or the secondpharmacologically active ingredient. In vitro release is preferablydetermined in accordance with Ph. Eur., preferably paddle method withsinker, 75 rpm, 37° C., 900 mL artificial gastric juice, pH 6.8.

The first pharmacologically active ingredient and/or the secondpharmacologically active ingredient may independently of one another bepresent in the pharmaceutical dosage form at least partially incontrolled-release form. For example, the first pharmacologically activeingredient and/or the second pharmacologically active ingredient may bereleased from the pharmaceutical dosage form in a prolonged manner, e.g.if administered orally, rectally or percutaneously. Such pharmaceuticaldosage forms are particularly useful for “once-daily” or “twice-daily”preparations, which only have to be taken once a day, respectively,twice a day. Suitable controlled-release materials are well known tothose skilled in the art.

The pharmaceutical dosage form according to the invention providingcontrolled release of the first pharmacologically active ingredientand/or the second pharmacologically active ingredient may be producedusing materials, means, devices and processes that are well known in theprior art of pharmaceutical dosage forms.

In order to obtain a solid pharmaceutical dosage form such as a tablet,for example, the pharmacologically active ingredients of thepharmaceutical composition may be granulated with a pharmaceuticalcarrier, for example conventional tablet ingredients such as cornstarch, lactose, saccharose, sorbitol, talcum, magnesium stearate,dicalcium phosphate or pharmaceutically acceptable gums, andpharmaceutical diluents, for example water, in order to form a solidcomposition that contains the pharmacologically active ingredients inhomogeneous distribution. The term “homogeneous distribution” is takento mean that the pharmacologically active ingredients are distributeduniformly over the entire composition, so that said composition mayeasily be divided into equally effective dose units, such as tablets,pills or capsules and the like. The solid composition is then dividedinto dose units. The tablets or pills of the pharmaceutical compositionaccording to the invention may also be coated or compounded in adifferent manner, in order to provide a dosage form with a controlledrelease.

If one of the pharmacologically active ingredients is to be releasedprior to the other pharmacologically active ingredient, for example atleast 30 minutes or 1 hour beforehand, pharmaceutical dosage formshaving a corresponding release profile may be prepared. An example ofsuch a pharmaceutical dosage form is an osmotically-driven releasesystem for achieving a delayed release of either the first or the secondpharmacologically active ingredient from an inner part (core) of thepharmaceutical dosage form via a coating that itself contains the otherpharmacologically active ingredient which is accordingly releasedearlier. In a release system of this kind, which is particularlysuitable for oral administration, at least part, and preferably all, ofthe surface of the release system, preferably those parts that will comeinto contact with the release medium, is/are semipermeable, preferablyequipped with a semipermeable coating, so the surface(s) is/arepermeable to the release medium, but substantially, preferably entirely,impermeable to the pharmacologically active ingredient contained in thecore, the surface(s) and/or optionally the coating comprising at leastone opening for releasing the pharmacologically active ingredientcontained in the core. Moreover, precisely that/those surface(s) thatis/are in contact with the release medium is/are provided with a coatingcontaining and releasing the other pharmacologically active ingredient.This is preferably taken to mean a system in tablet form comprising arelease opening, a core containing the first or the secondpharmacologically active ingredient, a polymer portion that exertspressure upon swelling, a semipermeable membrane and a coatingcontaining the other pharmacologically active ingredient. Embodimentsand examples of osmotically-driven release systems are, for example,disclosed in U.S. Pat. Nos. 4,765,989, 4,783,337 and 4,612,008.

A further example of a suitable pharmaceutical dosage form is agel-matrix tablet. Suitable examples are provided in U.S. Pat. Nos.4,389,393, 5,330,761, 5,399,362, 5,472,711 and 5,455,046. Particularlysuitable is a retarding matrix dosage form, with an inhomogeneousdistribution of the pharmaceutical composition, whereby, for example,one pharmacologically active ingredient, i.e. the first or the secondpharmacologically active ingredient, is distributed in the outer region(the portion that comes into contact with the release medium mostquickly) of the matrix and the other pharmacologically active ingredientis distributed inside the matrix. On contact with the release medium,the outer matrix layer initially (and rapidly) swells and firstlyreleases the pharmacologically active ingredient contained therein,followed by the significantly (more) controlled release of the otherpharmacologically active ingredient. Examples of a suitable matrixinclude matrices with 1 to 80% by weight of one or more hydrophilic orhydrophobic polymers as pharmaceutically acceptable matrix formers.

Preferably, the pharmaceutical dosage form according to the inventionprovides immediate release of the first pharmacologically activeingredient, and immediate or controlled release of the secondpharmacologically active ingredient.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention provides immediate release of both, the first and thesecond pharmacologically active ingredient. In this particular case, amultiple daily administration, in particular an administration twicedaily, thrice daily, or up to six times a day is preferred.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention provides immediate release of the firstpharmacologically active ingredient, and controlled release of thesecond pharmacologically active ingredient. This release profile may berealized by employing the aforementioned methods, e.g. theosmotically-driven release system providing the first pharmacologicallyactive ingredient in the coating and the second pharmacologically activeingredient in the core, or the retarding matrix dosage form containingthe first pharmacologically active ingredient in the outer matrix layerand the second pharmacologically active ingredient in the inside of thematrix.

In yet another preferred embodiment, the pharmaceutical dosage formaccording to the invention provides controlled release of both the firstand the second pharmacologically active ingredient.

In a further aspect, the invention relates to the use of thepharmaceutical composition according to the invention, and thepharmaceutical dosage form according to the invention respectively, inthe prevention or treatment of pain, anxiety or epilepsy.

In a preferred embodiment, the pharmaceutical composition according tothe invention and the pharmaceutical dosage form according to theinvention, respectively, are for use in the treatment of pain, whereinthe pain is preferably

-   peripheral, central or muscle skeletal pain; and/or-   acute, subacute or chronic pain; and/or-   moderate to severe pain; and/or-   neuropathic or psychogenic or nociceptive or mixed pain; and/or-   low back pain, visceral pain or headache; and/or-   post-operative (post-surgical), cancer or inflammatory pain.

For the purpose of specification, “acute pain” preferably refers to painthat lasts up to about 4 weeks, “subacute pain” preferably refers topain that lasts from more than about 4 weeks to about 12 weeks, and“chronic pain” preferably refers to pain that lasts for more than about12 weeks.

Preferably, the pain is selected from the group consisting of cancerpain, peripheral neuropathic pain, osteoarthritis, chronic visceralpain, neuropathic pain (diabetic polyneuropathy, HIV-associatedneuropathic pain, posttraumatic neuropathic pain, postherpeticneuralgia, chemotherapy associated pain), postzosteric neuralgia,postoperative neuropathic pain, inflammatory pain, migraine, low-backpain, fibromyalgia and trigeminal neuralgia.

In a preferred embodiment, the pain is chronic pain, in particularchronic nociceptive pain and/or chronic inflammatory pain.

In another preferred embodiment, the pain is non-chronic or acute pain,in particular post-operative pain (post-surgical pain).

In a further preferred embodiment, the pain is selected from the groupconsisting of diabetic polyneuropathy, postzosteric neuralgia,postoperative neuropathic pain, low-back pain and fibromyalgia.

In the following, the doses of the first and the secondpharmacologically active ingredient are again expressed according to thenumber of administrations “n” per day, i.e. the number ofadministrations of the pharmaceutical dosage form according to theinvention in the course of 24 hours.

In a preferred embodiment, the pharmaceutical dosage form is for use inthe treatment of neuropathic pain which may be optionally superimposedby nociceptive pain, where the dose of the first pharmacologicallyactive ingredient contained in the pharmaceutical dosage form preferablyis in the range of 1/n μg to 800/n μg or 1/n μg to 600/n μg or 1/n μg to400/n μg or 1/n μg to 250/n μg, more preferably in the range of 5/n μgto 150/n μg, even more preferably in the range of 10/n μg to 100/n μg,most preferably in the range of 20/n μg to 80/n μg and in particularmost preferably in the range of 30/n μg to 50/n μg. According to thisembodiment, the dose of the second pharmacologically active ingredientcontained in the pharmaceutical dosage form preferably is in the rangeof 500/n mg to 8,000/n mg.

In a preferred embodiment, in particular when the pharmaceutical dosageform is for use in the treatment of neuropathic pain and the secondpharmacologically active ingredient is paracetamol, the dose of thefirst pharmacologically active ingredient contained in thepharmaceutical dosage form preferably is in the range of 1/n μg to 800/nμg or 1/n μg to 600/n μg or 1/n μg to 400/n μg or 1/n μg to 250/n μg,more preferably in the range of 5/n μg to 150/n μg, even more preferablyin the range of 10/n μg to 100/n μg, most preferably in the range of20/n μg to 80/n μg and in particular most preferably in the range of30/n μg to 50/n pg; and the dose of the second pharmacologically activeingredient contained in the pharmaceutical dosage form preferably is inthe range of 500/n mg to 4,000/n mg, more preferably in the range of750/n mg to 3,900/n mg, even more preferably in the range of 1,000/n mgto 3,800/n mg, most preferably in the range of 1,500/n mg to 3,650/n mgand in particular in the range of 2,000/n mg to 3,500/n mg.

In another preferred embodiment, in particular when the pharmaceuticaldosage form is for use in the treatment of neuropathic pain and thesecond pharmacologically active ingredient contained in thepharmaceutical dosage form is propacetamol, the dose of the firstpharmacologically active ingredient preferably is in the range of 1/n μgto 800/n μg or 1/n μg to 600/n μg or 1/n μg to 400/n μg or 1/n μg to250/n μg, more preferably in the range of 5/n μg to 150/n μg, even morepreferably in the range of 10/n μg to 100/n μg, most preferably in therange of 20/n μg to 80/n μg and in particular most preferably in therange of 30/n μg to 50/n μg; and the dose of the secondpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 1,000/n mg to 8,000/n mg, morepreferably in the range of 1,500/n mg to 7,800/n mg, even morepreferably in the range of 2,000/n mg to 7,600/n mg, most preferably inthe range of 3,000/n mg to 7,300/n mg and in particular in the range of4,000/n mg to 7,000/n mg.

In another preferred embodiment, the pharmaceutical dosage form is foruse in the treatment of nociceptive pain which may be optionallysuperimposed by neuropathic pain, where the dose of the firstpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 50/n μg to 2,000/n μg or 50/nμg to 1,400/n μg or 50/n μg to 1,200/n μg or 50/n μg to 1,000/n μg, morepreferably in the range of 100/n μg to 800/n μg, still more preferablyin the range of 150/n μg to 650/n μg, even more preferably in the rangeof 250/n μg to 550/n μg, and most preferably in the range of 350/n μg to450/n μg. According to this embodiment, the dose of the secondpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 500/n mg to 8,000/n mg.

In a preferred embodiment, in particular when the pharmaceutical dosageform is for use in the treatment of nociceptive pain and the secondpharmacologically active ingredient is paracetamol, the dose of thefirst pharmacologically active ingredient contained in thepharmaceutical dosage form preferably is in the range of 50/n μg to2,000/n μg or 50/n μg to 1,400/n μg or 50/n μg to 1,200/n μg or 50/n μgto 1,000/n μg, more preferably in the range of 100/n μg to 800/n μg,still more preferably in the range of 150/n μg to 650/n μg, even morepreferably in the range of 250/n μg to 550/n μg, and most preferably inthe range of 350/n μg to 450/n μg; and the dose of the secondpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 500/n mg to 4,000/n mg, morepreferably in the range of 750/n mg to 3,900/n mg, even more preferablyin the range of 1,000/n mg to 3,800/n mg, most preferably in the rangeof 1,500/n mg to 3,650/n mg and in particular in the range of 2,000/n mgto 3,500/n mg.

In another preferred embodiment, in particular when the pharmaceuticaldosage form is for use in the treatment of nociceptive pain and thesecond pharmacologically active ingredient is propacetamol, the dose ofthe first pharmacologically active ingredient contained in thepharmaceutical dosage form preferably is in the range of 50/n μg to2,000/n μg or 50/n μg to 1,400/n μg or 50/n μg to 1,200/n μg or 50/n μgto 1,000/n μg, more preferably in the range of 100/n μg to 800/n μg,still more preferably in the range of 150/n μg to 650/n μg, even morepreferably in the range of 250/n μg to 550/n μg, and most preferably inthe range of 350/n μg to 450/n μg; and the dose of the secondpharmacologically active ingredient contained in the pharmaceuticaldosage form preferably is in the range of 1,000/n mg to 8,000/n mg, morepreferably in the range of 1,500/n mg to 7,800/n mg, even morepreferably in the range of 2,000/n mg to 7,600/n mg, most preferably inthe range of 3,000/n mg to 7,300/n mg and in particular in the range of4,000/n mg to 7,000/n mg.

Preferably, the pharmaceutical composition contains the first and thesecond pharmacologically active ingredient in such a weight ratio thatthey will exert a synergistic therapeutic effect upon administration toa patient. Thereby, the term “synergistic therapeutic effect” may referto a synergistic therapeutic effect with respect to the prevention ortreatment of pain (synergistic analgesic effect), a synergistictherapeutic effect with respect to the prevention or treatment ofanxiety (synergistic anxiolytic effect) as well as a synergistictherapeutic effect with respect to the prevention or treatment ofepilepsy (synergistic anti-convulsive effect). Suitable weight ratios ofthe pharmacologically active ingredients generating the synergistictherapeutic effect can be determined by methods well known to thoseskilled in the art.

A further aspect of the invention relates to a method of treating orpreventing pain, anxiety or epilepsy comprising the preferably twicedaily or once daily, preferably oral administration of thepharmaceutical dosage form according to the invention to a subject inneed thereof.

In a particular preferred embodiment,

-   -   the first pharmacologically active ingredient is        (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine        according to formula (I) in form of its free base, or a        hemicitrate, hydrochloride or maleate salt thereof; and/or    -   the second pharmacologically active ingredient is paracetamol;        and/or    -   the pharmaceutical composition and the pharmaceutical dosage        form, respectively, contain the first pharmacologically active        ingredient in a dose of from 20 μg to 80 μg or of from 80 μg to        200 μg or of from 200 μg to 800 μg or of from 800 μg to 1,200        μg; and/or    -   the pharmaceutical composition and the pharmaceutical dosage        form, respectively, contain the second pharmacologically active        ingredient in a dose of from 200 mg to 7,000 mg, in particular        in a dose of from 500 mg to 4,000 mg; and/or    -   the relative weight ratio of the first pharmacologically active        ingredient to the second pharmacologically active ingredient is        within the range of from 1:30 to 1:1,000,000, preferably 1:1,000        to 1:500,000 in the pharmaceutical composition and the        pharmaceutical dosage form, respectively; and/or    -   the pharmaceutical composition is for use in the treatment of        pain; and/or    -   the pharmaceutical composition is for use in the treatment of        pain, wherein the pain is peripheral, central or muscle skeletal        pain; and/or acute, subacute or chronic pain; and/or moderate to        severe pain; and/or neuropathic or psychogenic or nociceptive or        mixed pain; and/or low back pain, visceral pain or headache;        and/or post-operative (post-surgical), cancer or inflammatory        pain; and/or    -   the pharmaceutical composition and the pharmaceutical dosage        form, respectively, contain the first pharmacologically active        ingredient and the second pharmacologically active ingredient in        such a weight ratio that upon administration to a patient they        will exert a synergistic therapeutic effect; and/or    -   the pharmaceutical dosage form provides immediate release of the        first pharmacologically active ingredient in vitro in accordance        with Ph. Eur.; and/or    -   the pharmaceutical dosage form provides immediate or controlled        release of the second pharmacologically active ingredient in        vitro in accordance with Ph. Eur.; and/or    -   the pharmaceutical dosage form is for oral administration;        and/or    -   the pharmaceutical dosage form is for administration once, twice        or thrice daily, or four times daily.

In a further aspect, the invention relates to a kit comprising a firstpharmaceutical dosage form comprising the first pharmacologically activeingredient as described above, and a second pharmaceutical dosage formcomprising the second pharmacologically active ingredient as describedabove.

A suitable embodiment is a kit in which the first pharmaceutical dosagefrom comprising the first pharmacologically active ingredient and thesecond pharmaceutical dosage form comprising the secondpharmacologically active ingredient, although spatially separated, areprovided in a common presentation form, e.g. packaging.

Preferably, the first and the second pharmaceutical dosage form areadapted for simultaneous or sequential administration, wherein the firstpharmaceutical dosage form may be administered before or after thesecond pharmaceutical dosage form and wherein the first and the secondpharmaceutical dosage form are administered either via the same or adifferent pathway of administration.

For the purpose of specification, the term “simultaneous administration”preferably refers to an administration of the first and the secondpharmaceutical dosage form within a time span of 15 minutes from eachother, whereas the term “sequential administration” preferably refers toan administration of the first and the second pharmaceutical dosage formwithin a time span of more than 15 minutes from each other.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are adapted for administration to the patient via the samepathway.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are adapted for administration to the patient via differentpathways.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are administered simultaneously.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are administered sequentially.

In a preferred embodiment, the first and/or the second pharmaceuticaldosage form are adapted for once daily administration.

In another preferred embodiment, the first and/or the secondpharmaceutical dosage form are adapted for multiple dailyadministration, in particular twice daily or thrice daily.

In a preferred embodiment, the first pharmaceutical dosage form isadapted for once daily administration and the second pharmaceuticaldosage form is adapted for multiple daily, in particular twice daily orthrice daily, administration.

Suitable pathways of administration of the pharmaceutical dosage formscontained in the kit include but are not limited to oral, intravenous,intraperitoneal, intradermal, intrathecal, intramuscular, intranasal,transmucosal, subcutaneous, and/or rectal administration.

In a preferred embodiment, one or both of the pharmaceutical dosageforms contained in the kit are for oral administration.

In another preferred embodiment, one or both of the pharmaceuticaldosage forms contained in the kit are for parenteral administration, inparticular intravenous, intraperitoneal, intrathecal, intramuscular, orsubcutaneous administration.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are for oral, simultaneous administration once daily.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are for oral, simultaneous administration multiple daily, inparticular twice daily, thrice daily or four times daily.

In still another preferred embodiment, the first and the secondpharmaceutical dosage form are each for oral, sequential administrationonce daily.

In a preferred embodiment, the first and the second pharmaceuticaldosage form are for sequential administration once daily each, where thefirst and the second pharmaceutical dosage form are adapted foradministration via different pathways, e.g. oral and parenteraladministration.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are each for oral, sequential administration multiple daily,in particular twice daily, thrice daily or four times daily.

In another preferred embodiment, the first and the second pharmaceuticaldosage form are for sequential administration multiple daily each, inparticular twice daily, thrice daily or four times daily, where thefirst and the second pharmaceutical dosage form are adapted foradministration via different pathways, e.g. oral and parenteraladministration.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

Pharmacological methods:

In the following, the first pharmacologically active ingredient(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminewas employed in form of the hemicitrate salt. Therefore, all amounts ofthe first pharmacologically active ingredient are specified with respectto the hemicitrate salt.

As the second pharmacologically active ingredient, Paracetamol wasemployed.

EXAMPLE 1 Paw Incision Model in Rats (Postoperative Pain)

The experiments were carried out in male albino rats (Sprague Dawley)with 170 g-230 g body weight from a commercial breeder (Janvier;France). The animals were housed under standardized conditions:light/dark rhythm (06.00 h-18.00 h light, 18.00 h-06.00 h dark); roomtemperature 20° C.-24° C.; relative air humidity 35%-70%; 15 air changesper hour, air movement <0.2 m/sec. The animals were given tap water anda diet of standard laboratory food (Ssniff R/M-Haltung, SsniffSpezialdiäten GmbH, Soest, Germany) ad libitum. Both were withdrawnduring the test. All rats were used only once. Ten rats were used perexperimental group. There were at least five days between delivery ofthe animals and the day of surgery.

The rats were placed in a plastic cage with a wire mesh bottom whichallowed full access to the paws. Hind paw withdrawal threshold aftermechanical stimulation was tested with electronic von Frey hairs(Somedic Sales AB, Hörby, Sweden). Animals were placed in a plastic cagewith a wire mesh bottom which allowed full access to the paws.Behavioral accommodation was allowed for 30 min. In each case,withdrawal response was measured at an area adjacent to the wound(ipsilateral) and to the same area on the non-injured foot(contralateral). Two hours after surgery, primary hypersensitivity wastested as tactile withdrawal threshold shortly before drugadministration and at different time points after drug application.Animals injected with vehicle served as controls. The pretestmeasurement was made prior to surgery and two thresholds were taken pertest and averaged.

Surgery was performed as previously described (Brennan T. J.,Vandermeulen E. P., and Gebhart G. F., Characterization of a rat modelof incisional pain, Pain 1996; 64:493-501). Briefly, rats wereanaesthetised with isoflurane, and a 1 cm longitudinal incision wasmade, through skin and fascia of the plantar aspect of the foot,starting from the proximal edge of the heel and extending toward themetatarsal toes. The plantaris muscle was elevated and incisedlongitudinally. The muscle origin and insertion remained intact. Afterspreading of the muscle and haemostasis with gentle pressure, the skinwas closed with two single interrupted sutures. After surgery, the ratswere allowed to recover in their home cages and the animals regainedconsciousness within 2 to 5 minutes. In order to ensure a completerecovery from anaesthesia the baseline value of each individual animalwas recorded not until 2 hours after surgery.

The first pharmacologically active ingredient was dissolved in 5% DMSOand 95% glucose solution (5%). The second pharmacologically activeingredient was dissolved in 1% CMC in aqua dest. Intravenous (i.v.) andintraperitoneal (i.p.) applications were made in a volume of 5 mL/kg.

Data were recorded and the median was calculated from five values ofeach animal and measurement.

The median values of the individual latencies are calculated as thepercentage of the Maximum Possible Effect (% MPE) according to thefollowing formula: % MPE=100=[(value after application=pretest beforesurgery)/(pretest after surgery=pretest before surgery)·100]

The individual % MPE values were averaged for the respective treatmentgroup and expressed as mean % MPE±standard error of the mean (SEM).

The pharmacologically active ingredients were administered using alogarithmically staggered dose scheme. The results are presented ingraphs as means±SEM against the time after surgery.

Data were analyzed by means of two-factor analysis of variance (ANOVA)with repeated measures. Significance of treatment-, time- ortreatment×time interaction effects was analyzed by means of Wilks'Lambda statistics. In case of a significant treatment effect, pair-wisecomparison was performed at the different time points effect by Fisher'sleast significant difference test. Results were considered statisticallysignificant if p<0.05.

The interaction studies presented herein were performed by comparison ofthe theoretically additive effect of defined doses of the first and thesecond pharmacologically active ingredient with the experimentaldetermined effect of their combination.

The application route was intravenous (i.v.) for the firstpharmacologically active ingredient and intraperitoneal (i.p.) for thesecond pharmacologically active ingredient.

Tests were performed using doses of 0.00464 mg/kg body weight to 0.0068mg/kg body weight of the first pharmacologically active ingredient and215 mg/kg body weight of Paracetamol as the second pharmacologicallyactive ingredient.

When administered in combination, the first pharmacologically activeingredient (0.00464 mg/kg body weight i.v.) and the secondpharmacologically active ingredient (Paracetamol, 215 mg/kg body weighti.p.) showed an analgesic efficacy with a maximal effect of 33% MPE at30 min. The analysis showed additive interaction of the firstpharmacologically active ingredient and the second pharmacologicallyactive ingredient.

When administered in combination, a dose of 0.0068 mg/kg body weight(i.v.) of the first pharmacologically active ingredient and a dose of215 mg/kg body weight (i.p.) of the second pharmacologically activeingredient led to side effects (sedation).

FIG. 1 shows the withdrawal threshold in g in dependence of the timeelapsed after administration.

FIG. 2 shows % MPE (Maximum possible effect) of the first and the secondpharmacologically active ingredient and of the combined administrationof the first and the second pharmacologically active ingredient, and thetheoretical % MPE of the combined administration of the first and thesecond pharmacologically active ingredient in dependence of the timepost administration.

dose [mg/kg]

first pharmacologically active ingredient 0.00464

second pharmacologically active ingredient 215

combined administration of first 0.00464 + 215 pharmacologically activeingredient + second pharmacologically active ingredient

theoretical additive value of first pharmacologically activeingredient + second pharmacologically active ingredient

Experimental results demonstrating additive effect of the combination ofthe first and the second pharmacologically active ingredient aresummarized in the following tables 1 to 5.

TABLE 1 % MPE (Maximum possible effect) of the combined administrationof different doses of the first and the second pharmacologically activeingredient in dependence of the time post administration: % MPE 30 min.60 min. 90 min. dose (n = 10) (n = 10) (n = 10) [mg/kg] Mean SEM MeanSEM Mean SEM vehicle    0.0 + 0.0 −0.48 ± 0.71  −1.14 ± 0.65  0.47 ±1.45 Combination of first 0.00464 + 215 33.1 ± 6.71 6.13 ± 3.49 4.35 ±2.40 pharmacologically active p ≤ 0.001 p ≤ 0.05  n.s. ingredient andsecond  0.0068 + 215 41.2 ± 8.14 17.0 ± 2.56 3.46 ± 1.32pharmacologically active p ≤ 0.001 p ≤ 0.001 n.s. ingredient p: level ofstatistical significance; n.s.: not significant

TABLE 2 % MPE: GLM Repeated Measures and Statistical evaluation of thedata following two-factor analysis of variance (ANOVA) and Fisher's LSD:GLM (General Linear Model) %MPE treatment time interaction F(2, 22) =15.465 F(2, 44) = 37.591 F(4, 44) = 11.904 p < 0.001 p < 0.001 p < 0.001ANOVA [Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.00464 + 215p < 0.001 p = 0.043 p = 0.150  0.0068 + 215 p < 0.001 p < 0.001 p =0.358 p: level of statistical significance.

TABLE 3 ipsilateral: GLM Repeated Measures and Statistical evaluation ofthe data following two-factor analysis of variance (ANOVA) and Fisher'sLSD: GLM (General Linear Model) ipsilateral treatment time interactionF(2, 22) = 11.006 F(2, 44) = 37.049 F(4, 44) = 12.008 p < 0.001 p <0.001 p < 0.001 ANOVA [Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90min. 0.00464 + 215 p < 0.001 p = 0.111 p = 0.398  0.0068 + 215 p < 0.001p < 0.01  p = 0.732 p: level of statistical significance.

TABLE 4 contralateral: GLM Repeated Measures and Statistical evaluationof the data following two-factor analysis of variance (ANOVA) andFisher's LSD: GLM (General Linear Model) contralateral treatment timeinteraction F(2, 22) = 6.464 F(2, 44) = 13.172 F(4, 44) = 4.617 p <0.001 p < 0.001 p = 0.003 ANOVA [Fisher's LSD] dose [mg/kg] 30 min. 60min. 90 min. 0.00464 + 215 p = 0.004 p = 0.059 p = 0.356  0.0068 + 215 p= 0.051 p = 0.057 p < 0.001 p: level of statistical significance.

TABLE 5 % MPE (Maximum possible effect) of the first and the secondpharmacologically active ingredient and of the combined administrationof the first and the second pharmacologically active ingredient, and thetheoretical % MPE of the combined administration of the first and thesecond pharmacologically active ingredient in dependence of the timepost administration: % MPE 30 min. 60 min. 90 min. dose (n = 10) (n =10) (n = 10) [mg/kg] Mean SEM Mean SEM Mean SEM first pharmacologically0.00464 12.2 ± 2.69 10.6 ± 3.51  2.88 ± 2.27 active ingredient secondpharmacologically 215 16.3 ± 3.06 4.35 ± 1.53 −0.21 ± 0.75 activeingredient combination of first 0.00464/215 33.1 ± 6.71 6.13 ± 3.49 4.35± 2.4 pharmacologically active (theoretical (theoretical (theoreticalingredient and second additive value: additive value: additive value:pharmacologically active 28.5 ± 4.07) 15.0 ± 3.83) 2.67 ± 2.39)ingredient p = 0.507 p = 0.032 p = 0.502

EXAMPLE 2 Randall Selitto Test in Rats (Chronic Inflammatory Pain)

The weight ratios of the first and the second pharmacologically activeingredient that will lead to a supra-additive effect (synergisticeffect) may be determined via the test of Randall and Selitto asdescribed in Arch. Int. Pharmacodyn., 1957, 111: 409-419, which is amodel for inflammatory pain. The respective part of the literature ishereby incorporated by reference and forms part of the presentdisclosure.

By means of injection of 0.1 ml of Carrageenin-suspension ventrally intoa hind paw of a rat an oedema is induced, on which pain is generated 4hours later by continuously increasing pressure with a stamp (2 mm tipdiameter). The antinociceptive and antihyperalgesic activity of thetested pharmacologically active ingredient is determined at differentpoints in time after administration of the pharmacologically activeingredient. The measured value to be determined and at the same timealso the end point of the pain test is the pressure at which thevocalisation reaction of the rat occurs. The percentage maximum possibleeffect (% MPE) is calculated. The maximum pressure of the stamp is 250g. The group size is n=12.

ED₅₀-values were determined by regression analysis in case ofdose-dependent results (according to Litchfield J. T. and Wilcoxon F.A., A simplified method of evaluating dose-effect experiments, J.Pharmacol. Exp. Ther. 1949; 96: 99-113). The analysis of the resultswith respect to a supra-additive effect of the first and the secondpharmacologically active ingredient is carried out via statisticalcomparison of the theoretical additive ED₅₀-value with theexperimentally determined ED50-value of a so-called fixed ratiocombination (isobolographic analysis according to Tallarida J. T.,Porreca F., and Cowan A., Statistical analysis of drug-drug andsite-site interactions with isobolograms, Life Sci. 1989; 45: 947-961).

The interactions studies presented herein were performed usingequieffective doses of the first and the second pharmacologically activeingredient, calculated from the ratio of the respective ED₅₀ values ofthe first and the second pharmacologically active ingredient ifadministered alone.

The application route was intravenous (i.v.) for the firstpharmacologically active ingredient and intraperitoneal (i.p.) for thesecond pharmacologically active ingredient. The first and the secondpharmacologically active ingredient were dissolved in 5% DMSO, 5%Cremophor, 90% glucose solution (5%) and in 1% CMC in aqua dest.,respectively. Intravenous (i.v.) and intraperitoneal (i.p.) applicationswere made in a volume of 5 mL/kg.

In case of the combined, simultaneous administration, the relative doseratio of first pharmacologically active ingredient to the secondpharmacologically active ingredient was 1:56,453.

When the first pharmacologically active ingredient was applied alone,the peak effect was reached 15 min p. appl. (timepoint of firstmeasurement) and ED₅₀-value of 3.364 (2.896-3.815) μg/kg i.v. wascalculated. The second pharmacologically active ingredient Paracetamolinduced a dose-dependent analgesic effect with ED₅₀-value of 189,914(181,292-198,419) μg/kg i.p., reaching the peak effect 120 min p. appl.According to their respective timepoint of peak effect, the firstpharmacologically active ingredient was applied 15 min and the secondpharmacologically active ingredient 120 min before timepoint ofmeasurement of the interaction-experiments (i. e. the secondpharmacologically active ingredient was applied 105 min before the firstpharmacologically active ingredient). Thus, the time point of ED₅₀calculation of the pharmaceutical composition according to the inventioncorresponds to the timepoint of the peak effect of the respectivepharmacologically active ingredient. The isobolographic analysisrevealed that in case of the combined administration of the first andthe second pharmacologically active ingredient the experimentalED₅₀-values were significantly lower than the respective theoreticalED₅₀-values. Thus, the combination studies demonstrate significantsynergistic interaction of the first pharmacologically active ingredientwith the second pharmacologically active ingredient. The results of theisobolographic analysis are summarized in the following table 6.

FIG. 3 shows the graphical analysis of experimental ED₅₀-valuescorresponding to the single administration of the firstpharmacologically active ingredient and the second pharmacologicallyactive ingredient, respectively, and the corresponding theoreticadditive values for the combined administration of the first and thesecond pharmacologically active ingredient compared to the experimentalED₅₀-values determined for said combination.

-   -   ED₅₀ (95% CI)[μg/kg] (i.v./i.p.)    -   first pharmacologically active ingredient=3.36 (2.90-3.82)    -   second pharmacologically active ingredient=189,914        (181,292-198,419)    -   theoretical additive value=94,957 (88,212-101,701)    -   part of first pharmacologically active ingredient=1.68        (1.56-1.80)    -   part of second pharmacologically active ingredient=94,955        (88,211-101,700)    -   experimental value of the combination=68,427 (64,864-71,835)    -   part of first pharmacologically active ingredient=1.21        (1.05-1.38)    -   part of second pharmacologically active ingredient=68,426        (65,340-71,511)

TABLE 6 Experimental ED₅₀ values of the first and the secondpharmacologically active ingredient and isobolographic analysis of theinteraction between the first and the second pharmacologically activeingredient: Substance/ED₅₀ [μg/kg] (confidence interval) first secondTheoretical ED₅₀ Experimental ED₅₀ pharmacologically pharmacologically[μg/kg] of the [μg/kg] of the active ingredient active ingredientcombination combination Interaction 3.36 189,914 94,957 68,427 supra-(2.90-3.82) (181,292-198,419) (88,212-101,701) (64,864-71,835) additive(p < 0.001) p: level of statistical signifigance.

1. A pharmaceutical composition comprising: (a) a firstpharmacologically active ingredient selected from(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand the physiologically acceptable salts thereof, and (b) a secondpharmacologically active ingredient selected from paracetamol andpropacetamol.
 2. The pharmaceutical composition according to claim 1,wherein the first pharmacologically active ingredient is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminein form of the hydrochloride, hemicitrate or maleate salt.
 3. Thepharmaceutical composition according to claim 1 or 2, wherein the secondpharmacologically active ingredient is paracetamol.
 4. Thepharmaceutical composition according to any of the preceding claims,which contains the first and the second pharmacologically activeingredient in such a weight ratio that they will exert a synergistictherapeutic effect upon administration to a patient.
 5. Thepharmaceutical composition according to any of the preceding claims,wherein the relative weight ratio of the first pharmacologically activeingredient to the second pharmacologically active ingredient is withinthe range of from 1:30 to 1:1,000,000.
 6. The pharmaceutical compositionaccording to any of the preceding claims for use in the prevention ortreatment of pain, anxiety or epilepsy.
 7. The pharmaceuticalcomposition according to claim 6, wherein the pain is: peripheral,central or muscle skeletal pain; and/or acute, subacute or chronic pain;and/or moderate to severe pain; and/or neuropathic or psychogenic ornociceptive or mixed pain; and/or low back pain, visceral pain orheadache; and/or post-operative (post-surgical), cancer or inflammatorypain.
 8. A pharmaceutical dosage form comprising the pharmaceuticalcomposition according to any of the preceding claims.
 9. Thepharmaceutical dosage form according to claim 8, which contains thefirst pharmacologically active ingredient in a dose of from 10 to 1,200μg.
 10. The pharmaceutical dosage form according to claim 8 or 9, whichcontains the second pharmacologically active ingredient in a dose offrom 100 to 8,000 mg.
 11. The pharmaceutical dosage form according toany of claims 8 to 10, wherein the dosage of the first pharmacologicallyactive ingredient is within the range of from 1:20 to 20:1 of the amountwhich is equieffective to the dosage of the second pharmacologicallyactive ingredient.
 12. The pharmaceutical dosage form according to anyof claims 8 to 11, which is for oral, intravenous, intraperitoneal,transdermal, intrathecal, intramuscular, intranasal, transmucosal,subcutaneous, or rectal administration.
 13. The pharmaceutical dosageform according to any of claims 8 to 12, which provides under in vitroconditions immediate release or controlled release of the firstpharmacologically active ingredient and/or the second pharmacologicallyactive ingredient.
 14. A kit comprising a first pharmaceutical dosageform comprising the first pharmacologically active ingredient as definedin claim 1 or 2, and a second pharmaceutical dosage form comprising thesecond pharmacologically active ingredient as defined in claim 1 or 3.15. The kit according to claim 14, wherein the first and the secondpharmaceutical dosage form are adapted for simultaneous or sequentialadministration, either by the same or a different pathway ofadministration.